A 26-day-old male infant presented with recurrent convulsions from 18 days of life. Laboratory investigations revealed severe hypomagnesemia (0.07 mmol/L) and hypocalcemia (1.65 mmol/L). Whole-exome sequencing was performed and identified compound heterozygous pathogenic variants in the TRPM6 gene, comprising c.5616G>A (p.Trp1872Ter) and a deletion of exons 20-23. The c.5616G>A variant was inherited from the father, and the exon 20-23 deletion was inherited from the mother; neither variant has been previously reported. Based on these findings, the diagnosis of primary hypomagnesemia with secondary hypocalcemia was confirmed. Oral magnesium sulfate supplementation was initiated, and no further convulsions occurred. At the 8-year follow-up, the patient exhibited persistent hypomagnesemia without other abnormalities. This case highlights that genetic testing helps confirm the diagnosis, and early magnesium supplementation effectively controls symptoms and prevents irreversible neurological impairment. 患儿男，日龄26 d，生后18 d起出现反复抽搐，实验室检查示严重低镁血症（0.07 mmol/L）及低钙血症（1.65 mmol/L）。全外显子组测序结果示患儿TRPM6基因存在c.5616G>A（p.Trp1872Ter）和外显子20~23缺失复合杂合致病性变异，其中前者来自父亲，后者来自母亲，且均未见文献报道。该患儿确诊为原发性肠性低镁血症，口服硫酸镁治疗后未再发抽搐。随访8年，仅表现为持续性低镁血症，余无异常。该病例提示，基因检测有助于明确诊断，早期补充镁剂可有效控制症状，并且可预防神经系统不可逆损伤。.

Hypomagnesemia type 1 (HOMG1) is a rare autosomal recessive condition due to TRPM6 gene mutation, leading to primarily impaired intestinal magnesium absorption resulting in secondary hypocalcemia. This study aimed to determine the clinical spectrum of hypomagnesemia with secondary hypocalcemia due to TRPM6 mutation. Retrospective study carried out for a period of 2 years at the Department of Pediatric Endocrinology and Diabetes, University of Child Health Sciences, The Children's Hospital, Lahore. All genetically confirmed cases of primary hypomagnesemia due to TRPM6 mutation were clinically and biochemically reviewed to look at their clinical spectrum. Eleven patients (n = 7 male) with homozygous TRPM6 mutation (7 novel variants) from ten different families were reported. Six cases (5 families) had a history of sibling death due to hypocalcemia seizures. Irritability and excessive crying were the first symptoms (mean age = 20 days) followed by intractable seizures (mean age = 2.07 months) in our cohort. Eight patients presented to tertiary care hospital under 6 months of age, 2 between 6 and 12 months, and 1 at 3 years of age. Initial biochemical profile in all cases revealed low magnesium, low calcium, normal/high phosphate, normal alkaline phosphatase, low/normal parathyroid hormone, normal/high 25-OH D level, and low fractional excretion of Mg. All were started on daily oral magnesium with the aim of achieving a normal biochemical profile including magnesium level. All cases are currently maintaining their bone profile on oral magnesium and are seizure free. HOMG1 due to TRPM6 mutation is a rare condition. We are reporting 11 cases of TRPM6 mutation due to 9 different variants (7 novel). Persistent severe secondary hypocalcemia is a prominent clinical feature of TRPM6 mutation, which can be life-threatening if not treated promptly.

Primary hypomagnesemia with secondary hypocalcemia (HSH) is caused by loss-of-function mutations in the TRPM6 gene encoding the epithelial magnesium channel. It is characterized by hypomagnesemia and secondary hypocalcemia associated with neurological symptoms. Here, we aimed to investigate the genetic defects of the TRPM6 gene found in a girl from China. The genomic DNA of the proband and the parents was extracted for whole-exome sequencing. Sanger sequencing was further performed to validate the candidate variants. Subsequently, the TRPM6 gene deletion was verified by quantitative PCR (qPCR) experiment. The effect of the variant on mRNA splicing was analyzed through a minigene splice assay and reverse transcription PCR (RT-PCR) in vitro. The proband presented with the symptoms of generalized seizures, tetany, and muscle spasms, which were refractory to anticonvulsant treatment. Phenotypic data indicated that the patient had hypomagnesemia, poor parathyroid hormone response, and resultant hypocalcemia. The trio whole-exome sequencing identified that the proband carried compound heterozygous variants in the TRPM6 gene, a paternally derived exon 6 deletion, and a maternally derived splicing variant (c.1638+7T>C) in exon 14. The minigene splice assay confirmed that the c.1638+7T>C variant resulted in exon 14 skipping, which caused the alteration of TRPM6 mRNA splicing. Our results support that the compound heterozygous variants in TRPM6 are responsible for HSH in this patient. A novel pathogenic splicing variant (c.1638+7T>C) in the intron 14 disturbs the normal TRPM6 mRNA splicing, suggesting that the non-classical splice variant plays a critical role in HSH. This variant is essential for future effective genetic diagnosis.

Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by biallelic variants in TRPM6 gene. In this study, we reported a Chinese patient diagnosed with HSH in Tianjin Children's Hospital. Detailed clinical examination and laboratory test were performed and whole exome sequencing (WES) was applied to detect the pathogenic gene in the proband. The suspected compound heterozygous variant in TRPM6 gene was verified by Sanger sequencing and quantitative real-time PCR technology. Minigene assay was performed to verify the function of the variant suspected to affect splicing process. The patient presented with seizure and markedly decreased levels of serum magnesium and calcium. WES combined with functional study diagnosed a pediatric patient with HSH caused by a compound heterozygous variant in TRPM6 gene, containing a novel non-canonical splicing-site variant c.5058-26A > G and a heterozygous deletion in exons 27-33 (chr9q21.13: 77357467-77376734). The compound heterozygous variant in TRPM6 gene is the pathogenic cause of the proband. The combined application of WES and functional study contribute to validating the effect of an uncertain genetic variant on splicing, improving the pathogenicity evidence and identifying the etiology of the disease. It is helpful for early diagnosis and treatment of HSH.

Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.